Usefulness of atezolizumab plus bevacizumab as second-line therapy for patients with unresectable hepatocellular carcinoma.

AIM: To clarify the efficacy of atezolizumab (ATZ) plus bevacizumab (BEV) as the second-line therapy for patients with unresectable hepatocellular carcinoma (HCC). METHODS: The subjects were 82 patients with HCC receiving ATZ/BEV, including 33 patients with previous therapies with molecular-targeted agents (MTA). Therapeutic efficacy was evaluated using contrast-enhanced CT according to the mRECIST. RESULTS: The Child-Pugh scores were 5, 6,7 and 8 in 40, 35, 5 and 2 patients, respectively, and the extents of HCC progression were BCLC stage A, B and C in 3, 31 and 48 patients, respectively. Early therapeutic efficacy was evaluated in 67 patients, and percentages of patients achieving CR/PR/SD/PD until 12 weeks were 3.0%/29.9%/49.3%/17.9%, respectively, indicating ORR of 32.8% and DCR of 82.1%, The ORR was higher in MTA-naïve patients (40.5%) than in those after discontinuation of lenvatinib due to PD (7.7%, P = 0.0410), while the DCR was equivalent between both patients (83.3% vs 80.0%, P = 0.1184), and the multivariate analysis revealed previous MTA therapies with lenvatinib alone as a factor to deteriorate the ORR (HR of 4.846 (P = 0.0619)). The OS rates at 24 and 48 weeks were 86% and 72%, respectively, and the rates did not differ between MTA-naïve and MTA-experienced patients. Multivariate analyses revealed that achievement of CR, PR or SD and peripheral neutrophil/lymphocyte ratio were associated with a favorable outcome (HR of 0.124, P<0.0001 and 0.351, P = 0.0303). CONCLUSIONS: ATZ/BEV merits consideration even for MTA-experienced patients, since the OS was equivalent to those in MTA-naïve patients despite of an unfavorable early therapeutic efficacy.

Long-term outcomes of patients with cirrhosis presenting with bleeding gastric varices.

AIM: To establish a therapeutic strategy for cirrhosis patients with gastric variceal bleeding. METHODS: The outcomes of 137 patients with bleeding gastric varices were evaluated. RESULTS: The bleeding source was gastroesophageal varices (GOV) in 86 patients, and gastric fundal varices (FV) in 51 patients. The Child-Turcotte-Pugh classes were A, B, and C in 26, 79, and 32 patients, respectively; 34 patients (24.8%) had hepatocellular carcinoma (HCC), of which 11 also had complicating portal venous tumor thrombosis (PVTT). Patients with GOV were treated by endoscopic variceal ligation or endoscopic injection sclerotherapy (EIS) with ethanolamine oleate, while those with FV were treated by EIS with cyanoacrylate; 29 patients with FV also underwent additional balloon-occluded retrograde transvenous obliteration (BRTO). Hemostasis was successfully achieved in 136 patients (99.3%), and the cumulative 1-year, 3-year, and 5-year rebleeding rates were 18.1%, 30.8%, and 30.8%, respectively, in the patients with GOV, and 2.2%, 12.5% and 12.5%, respectively, in the patients with FV. The overall 1-year, 3-year, and 5-year survival rates were 79.7%, 71.5% and 64.4%, respectively, in the patients with GOV, and 91.0%, 76.9% and 59.5%, respectively, in the patients with FV. Multivariable analysis identified PVTT and alcoholic cirrhosis as a significant risk factor associated with rebleeding, model for end-stage liver disease (MELD) score and PVTT as significant factors associated with survival. CONCLUSIONS: Endoscopic therapies with or without BRTO appeared to be useful therapeutic strategies to prevent rebleeding in patients with gastric variceal bleeding, and favorable outcomes were obtained, except in patients with underlying HCC associated with PVTT and/or severe liver damage.

Two Cases of Intraabdominal Bleeding Caused by Hepatocellular Carcinoma Rupture Soon after the Initiation of Chemotherapy with Lenvatinib.

We herein report two patients with hepatocellular carcinoma (HCC) who exhibited intraabdominal bleeding caused by tumor rupture soon after lenvatinib initiation. A hypervascular nodule was present in the lateral segment manifesting extrahepatic protrusion in an 81-year-old-man and in the caudate lobe, which was completely occupied by the tumor, in an 83-year-old-man. Both patients were given lenvatinib, and epigastralgia occurred suddenly three and five days later. Computed tomography revealed high-attenuation areas suggesting bleeding around the left and caudate lobes. Considering the strong antiangiogenic effects by lenvatinib, transcatheter arterial embolization should be performed before lenvatinib initiation in patients with subcapsular HCC.

Therapeutic efficacy of lenvatinib for patients with unresectable hepatocellular carcinoma based on the middle-term outcome.

AIM: This study sought to clarify the usefulness of lenvatinib for patients with unresectable hepatocellular carcinoma (HCC). METHODS: The subjects were 69 patients with HCC receiving lenvatinib; the median age was 73 years, and 14 and 67 patients had been previously treated with regorafenib and/or sorafenib and therapies without molecular-targeted agents, respectively. Therapeutic efficacy was evaluated using contrast-enhanced CT images obtained 4-8 weeks after the start of lenvatinib and the middle-term outcome using Kaplan-Meier method. RESULTS: The baseline Child-Pugh scores were 5, 6 and 7 in 31, 32 and 6 patients, respectively, and the modified albumin-bilirubin (mALBI) grades were 1, 2a and 2b in 20, 20 and 29 patients, respectively. The Barcelona Clinic Liver Cancer (BCLC) stages following downsizing after prior treatment were A, B and C in 17, 22 and 30 patients, respectively. The therapeutic efficacy was evaluated in 54 patients, and the percentages of patients achieving CR, PR, SD and PD were 3.7%, 44.4%, 37.0%, and 14.8%, respectively. The ALBI scores deteriorated significantly between 4 and 12 weeks after the start of therapy, compared with the baseline. The cumulative survival rates at 48 weeks were significantly higher among patients achieving CR/PR (95.5%) than among those showing no response (54.3%). Multivariate analyses revealed that the BCLC stages and the serum AFP levels were significantly associated with therapeutic efficacy, while the mALBI grade was associated with the middle-term outcome. CONCLUSIONS: A favorable middle-term outcome was obtained in patients with HCC receiving lenvatinib, especially in those manifesting grades 1/2a mALBI at baseline, despite the deterioration in ALBI scores during treatment.

Retreatment with sofosbuvir/ledipasvir with or without lead-in interferon-ß injections in patients infected with genotype 1b hepatitis C virus after unsuccessful daclatasvir/asunaprevir therapy.

AIM: To improve the therapeutic efficacy of sofosbuvir/ledipasvir (SOF/LDV) for the retreatment of patients after daclatasvir/asunaprevir (DCV/ASV), a customized therapy with or without lead-in interferon (IFN)-ß injections was formulated according to the types of resistance-associated substitutions (RAS) in the non-structural protein (NS)5A region of genotype 1b hepatitis C virus (HCV). METHODS: Thirty-three patients failing prior DCV/ASV received SOF/LDV for 12 weeks. Patients with HCV carrying unfavorable NS5A-RAS and/or those previously treated with simeprevir were given lead-in IFN-ß injections twice a day for 2 weeks; sequential changes in the NS5A-RAS during the injection period were evaluated using deep sequencing. RESULTS: Lead-in injections were not undertaken in 27 patients; a sustained viral response (SVR) was achieved in 26 patients, while viral relapse occurred in 1 patient with HCV carrying NS5A-L28M/R30H/Y93H mutations. Among the 6 patients receiving lead-in injections, viral relapse occurred in 2 patients who had an unfavorable IFN-λ3-related gene single nucleotide polymorphism allele; both patients had been previously treated with simeprevir, and HCV carrying NS5A-L31V/Y93H mutations had emerged after DCV/ASV. Deep sequencing revealed no changes in the NS5A-RAS profiles during the lead-in injection period in either patient. In contrast, in a patient with a favorable allele who was infected with similar unfavorable HCV strains, NS5A-L31/Y93 wild-type strains appeared during the injection period, enabling an SVR. CONCLUSION: Using customized therapies based on the NS5A-RAS profiles, a high SVR rate was obtained after SOF/LDV in patients failing prior DCV/ASV. Lead-in IFN-ß injections did not improve the efficacy in patients with HCV carrying unfavorable NS5A-RAS except in those with a favorable IFN-λ3-related gene allele.

Balloon-occluded retrograde transvenous obliteration as a procedure to improve liver function in patients with decompensated cirrhosis.

AIM: Portosystemic shunts aggravate liver function by decreasing portal blood flow. The usefulness of balloon-occluded retrograde transvenous obliteration (B-RTO), a standardized therapeutic procedure for gastric fundal varices (GFV), for the improvement of liver function was evaluated in cirrhotic patients with or without varices. METHODS: The subjects were 161 patients with portosystemic shunts. A balloon catheter was inserted into the shunts, followed by the injection of 5% ethanolamine oleate through the catheter under balloon inflation. The balloon was kept inflated for 6 to 48 h. RESULTS: B-RTO was performed as a therapy for GFV in 112 patients and for the improvement of liver function in 49 patients. The targets were splenorenal shunts in 104 patients (93.6%) in the former group and 33 patients (67.3%) in the latter group, and the procedures were successfully completed in 109 (97.3%) and 39 (79.6%) patients, respectively. In both groups, the serum albumin levels were increased and the serum ammonia levels were decreased at more than 1 month after the procedures, compared with the baseline levels, whereas significant improvements in the Child-Pugh scores and prothrombin times were only seen in the latter group. In these patients, the portal blood flows evaluated using Doppler ultrasound were increased at 1 week after the procedures, compared with the baseline levels. CONCLUSIONS: B-RTO is a useful therapeutic procedure for improving liver function even in patients without GFV by increasing the portal venous flow with successfully targeted, uncommon portosystemic shunts.